tbuckley/cabot-search huggingface dataset:
Preclinical evaluation of the safety and effectiveness of a new bioartificial cornea
Authors: Yansha Hao, Jingting Zhou, Ju Tan, Feng Xiang, Zhongliang Qin, Jun Yao, Gang Li, Mingcan Yang, Lingqin Zeng, Wen Zeng, Chuhong Zhu
Journal: Bioactive Materials (2023)

Cross-linking agents are frequently used to restore corneal properties after decellularization, and it is especially important to select an appropriate method to avoid excessive cross-linking. In addition, how to promote wound healing and how to improve scar formation require further investigation. To ensure the safety and efficacy of animal-derived products, we designed bioartificial corneas (BACs) according to the criteria for Class III medical devices. Our BACs do not require cross-linking agents and increase mechanical strength via self-cross-linking of aldehyde-modified hyaluronic acid (AHA) and carboxymethyl chitosan (CMC) on the surface of decellularized porcine corneas (DPCs). The results showed that the BACs had good biocompatibility and transparency, and the modification enhanced their antibacterial and anti-inflammatory properties in vitro. Preclinical animal studies showed that the BACs can rapidly regenerate the epithelium and restore vision within a month. After 3 months, the BACs were gradually filled with epithelial, stromal, and neuronal cells, and after 6 months, their transparency and histology were almost normal. In addition, side effects such as corneal neovascularization, conjunctival hyperemia, and ciliary body hyperemia rarely occur in vivo. Therefore, these BACs show promise for clinical application for the treatment of infectious corneal ulcers and as a temporary covering for corneal perforations to achieve the more time.
P1657: CANCER-ASSOCIATED NON-BACTERIAL THROMBOTIC ENDOCARDITIS AFFECTING RIGHT HEART VALVES AS POTENTIAL CAUSE OF PULMONARY EMBOLISM
Authors: Ewa Wysokinska, Patryk Patrzalek, Alladi Swetha, Damon Houghton, Reto Kurrman, David Hodge, Waldemar Wysokinski, Kyle Klarich
Journal: HemaSphere (2023)

Topic: 34. Thrombosis and vascular biology - Biology & Translational Research Background: Cancer-associated non-bacterial thrombotic endocarditis (Ca-NBTE) affects mainly mitral and aortic valves with very rare involvement of the right heart valves. Premortem description of these patients is limited to few case reports. Aims: To present first clinical series of patients with right heart valves affected by Ca-NBTE describing underlying cancers, type of valve lesions and embolic complications. Methods: An electronic search of Mayo Clinic records (03/31/2002-06/30/2022) with the subsequent manual review was performed to identify adult patients with echocardiographically detected NBTE, active cancer, and no infectious endocarditis or lupus anticoagulant/antiphospholipid antibodies Results: Out of 115 identified patients with Ca-NBTE (mean age 63.2±9.7 years, 66.1% female), there were 8 cases (7.0%) affecting right heart valves (mean age 64.5±12.1 years, 3 females) with underlying cancer: pancreatic (n=3), lung (n= 2), genitourinary (n=1), gastric (n=1) and neck sarcomatoid carcinoma (n=1). Tricuspid valve (TV) was affected in 8 patients and pulmonic valve (PV) in one case; 4 patients had Ca-NBTE limited only to PV, two patients had mitral valve and TV, one patient had mitral, aortic and TV, and one patient with pancreatic cancer had all four valves (mitral, aortic, TV, and PV) affected by NBTE. Six patients had embolic complications to the brain with one patient in that group also experiencing emboli to the kidney and spleen. Out of 4 patients with NBTE limited to TV, two still had brain emboli, one had only pulmonary embolism, and one patient had no embolic complications. 4 patients had pulmonary embolism as an embolic complication: Patient 1 with pancreatic cancer with all 4 valves affected was diagnosed with concurrent pulmonary embolism and lower extremity subacute DVT. Patient 2 with thrombotic multi lobed mass on TV had concurrent finding of multiple acute and subacute pulmonary emboli in both lungs. Lower extremity US with chronic DVT. Patient 3 had thrombotic changes involving tricuspid valve presenting as complex mass beneath the valve. CT scan of the abdomen showed right lower lobe pulmonary embolism. Patient 4 with both mitral and TV involvement had concurrent pulmonary embolism and DVT. Summary/Conclusion: Ca-NBTE affecting right heart valves represent 7% of all cases. In half of those cases, NBTE was limited to TV. Cancer profile was similar to those reported in left heart valve affection. Emboli complications were noticed within the brain, systemic arterial circulation, and pulmonary artery. Right-sided thrombotic endocarditis may be potential overlooked cause of pulmonary embolism and may be considered in patients with high-risk malignancy if lower extremity ultrasound is negative for DVT. Keywords: Pulmonary embolism, Cancer, Thrombosis
P1454: CLINICAL DETERMINANTS OF CARDIAC IRON IN REGULARLY TRANSFUSED THALASSEMIA INTERMEDIA PATIENTS
Authors: Antonella Meloni, Laura Pistoia, F. Mehtap Pasin, Sara Gentili, Marilena Serra, Michele Santodirocco, Vincenzo Spadola, Nicolò Schicchi, Massimiliano Missere, Alberto Cossu, Vincenzo Positano, Filippo Cademartiri
Journal: HemaSphere (2023)

Topic: 27. Thalassemias Background: In sporadically transfused or transfusion naïve thalassemia intermedia (TI) patients, myocardial iron overload (MIO) by T2* cardiac magnetic resonance (CMR) was demonstrated to be a highly rare finding, despite the significant hepatic iron accumulation. Studies specifically addressing this issue or the clinical correlates of cardiac T2* values only in regularly transfused TI patients are lacking. Aims: We assessed the clinical determinants of global heart T2* values in regularly transfused TI patients. Methods: We considered 154 beta-TI patients (42.53±13.83years, 88 females) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia project. Iron overload was quantified by a multiecho T2* technique. Results: Global heart T2* values were comparable between males and females as well as between patients without and with the spleen, but showed a weak positive correlation with aging (R=0.215, p=0.007). Global heart T2* values were inversely correlated with serum ferritin levels (R=-0.272, p=0.003) and with MR liver iron concentration (LIC) values (R=-0.240, p=0.039). Global heart T2* values showed no association with the duration of the transfusion therapy and a positive association with the duration of the chelation therapy (R=0.239, p=0.031). To detect the predictors of global heart T2* values, a stepwise regression analysis was performed, including in the model age, duration of chelation therapy, serum ferritin levels, and MRI LIC. Age and serum ferritin levels were the strongest predictors of global heart T2* values (F=18.24; p<0.0001). No variable was excluded from the multivariable models due to excessive collinearity. Applying the conservative 20 ms cut-off, the prevalence of significant MIO was 2.6%. When a more sensitive, protocol-specific cut-off (32 ms) was used, early MIO was found in 15 (9.7%) patients. At receiver-operating characteristic (ROC) curve analysis, a serum ferritin level>786 ng/ml predicted the presence of a pathological global heart T2* with a sensitivity=69.2% and a specificity=72.9% (p=0.042). The area under the curve was 0.69 (95% confidence intervals=0.61-0.78). Summary/Conclusion: In TI, regular transfusions increase the risk of MIO. Global heart T2* values showed a significant inverse correlation with both serum ferritin and hepatic iron levels and, surprisingly, the association with serum ferritin levels emerged as the strongest one. The introduced cut-off of 786 ng/ml may help to identify the patients at high risk for cardiac iron accumulation, in whom it would be prudent to escalate or modify the iron chelation therapy. Keywords: Iron overload, beta thalassemia
P513: MOLECULAR PATTERN BY AGE AND OVERALL SURVIVAL IN ACUTE MYELOID LEUKEMIA: A POPULATION-BASED STUDY FROM THE SWEDISH AML REGISTRY.
Authors: Gunnar Juliusson, Christer Nilsson, Sören Lehmann, Martin Jädersten, Lovisa Wennström, Linda Fogelstrand, Panagiotis Baliakas, Tatjana Pandzic, Lucia Cavelier, Anna Eriksson, Albin Österroos, Anna Thunström, Benedicte Piauger, Bertil Uggla, Emma Ölander, Gustav Orrsjö, Jörg Cammenga, Kristina Myhr-Eriksson, Petter Willner Hjelm, Stefan Deneberg, Thoas Fioretos, Martin Höglund, Vladimir Lazarevic
Journal: HemaSphere (2023)

Background: AML is mostly a disease of the elderly with a median age of 72 years, but most molecular data originate from clinical studies, usually with age restrictions. Aims: To report population-based data on mutations from the Swedish AML Registry by age and outcome. Methods: Selected gene mutations (FLT3-ITD, NPM1 and CEBPA) became possible to report to the registry in 2007. Extended gene analyses started in 2016 with whole-exome sequencing (WES) in a few research sites, and TruSight Myeloid Panel (54 genes), later exchanged for Twist (195 genes) in clinical practice, but reporting could not start until 2020. Mutation data from clinical routine were therefore retrospectively added to the registry through hospital genetic laboratory databases. Data was extracted from the Swedish AML Registry on January 3, 2023. Results: Among 6525 patients diagnosed since 2007 molecular data was available from 3326 (51%). Between 2016 and 2022 the proportion of patients with panel or WES data increased from 22% to 71%. Currently the registry contains panel/WES data from 73% of patients <65 years, 55% 65-79 years, 27% 80-84 years, and 10% 85 years, i.e., from 1579 patients with a median age of 68 years. The overall frequency of specific mutations was slightly different to other studies, probably due to the real-world age distribution. The mean number of mutations per patient was 3.4. Overall, mutations were less common in younger patients, 2.3/pat <40 yrs, 3.0 in patients 40-64 years, 3.7 in patients 65-74 yrs and 3.8 in patients 75+ years. Mutation rates were skewed by age for many genes (Figure). FLT3, CEBPA and NRAS were more frequently mutated in young patients, whereas NPM1, DNMT3A, IDH1/2, STAG2 and SRSF2 were rarely mutated in young. TET2, ASXL1 and TP53 were most frequently mutated in older. Among those with panel/WES-data, 69% received intensive, 22% hypomethylating agents, and 9% palliation only (median ages 63, 76 and 78 years, respectively). Overall survival according to molecular subtypes are shown in the Table. Summary/Conclusion: Our data show that the overall incidence of mutations increases by age up to 65 years, but thereafter remains stable, whereas certain genes have different age distributions. The strong impact of specific genetic alterations on survival in a large population-based study with real-life age distribution is shown. The clinical impact of combinations of specific mutations and karyotypes is being evaluated.Keywords: Mutation status, Age, Acute myeloid leukemia, Survival
P1496: TRANSFERRIN NON-CODING VARIANTS CAUSE MRNA DESTABILISATION IN CONGENITAL HYPOTRANSFERRINEMIA
Authors: Xenia Ferrer, Lídia Romero-Cortadellas, Cristina Diaz-de-Heredia, Katja Moser, Ilona Kleine Budde, Mayka Sanchez
Journal: HemaSphere (2023)

Topic: 29. Iron metabolism, deficiency and overload Background: Congenital hypotransferrinemia or atransferrinemia is an ultra-rare autosomal recessive hematologic disease caused by mutations in the transferrin (TF) gene that lead to a deficiency in transferrin, a serum glycoprotein responsible for proper iron transport in blood. Disease onset occurs in early childhood and is characterised by severe hypochromic microcytic anaemia and iron overload in non-hematopoietic tissues. To date, 20 cases of 18 families have been reported. Aims: We describe four new patients from two families of Spanish and Turkish origin, report four novel mutations (one missense, one frameshift, and two regulatory variants) and examine their functional consequences using molecular and computational methods. Methods: DNA from patients was analysed using a targeted next generation sequencing (NGS) gene panel containing the complete genomic region of the TF gene including all introns, promoter and regulatory regions. Data was analysed with SureCall software and processed for subsequent variant search and filtering. Putative pathogenic mutations were confirmed by Sanger sequencing. Luciferase assays and splicing functional studies were performed to study the expression of the TF mRNA. Results: In the Spanish family, the missense p.Ala418Glu mutation changes the electrostatic environment around the iron binding site of transferrin towards more hydrophobic. Splicing studies revealed that the intronic variant c.[2062 + 20T>G] results in the degradation of the mutated allele. In the Turkish family, the frameshift mutation p.Ala222Valfs*32 will lead to a truncated protein; and preliminary data suggest that the c.*53A>G mutation (located in the 3’UTR) creates a new target region for a miRNA (hsa-miR-4789-3p) and may destabilize the mRNA. Therefore, all reported mutations cause hypotransferrinemia by producing a non-functional transferrin. Summary/Conclusion: To the best of our knowledge, this is the first time that mutations in regulatory regions (intronic and 3’UTR) are described as causative for congenital hypotransferrinemia. Therefore, regulatory mutations should be considered in genetically unsolved congenital hypotransferrinemic patients where only one mutation has been identified after screening the entire coding region of the TF gene. Keywords: Iron deficiency anemia, Iron metabolism, Anemia, Iron overload
P1194: PROGNOSTIC SIGNIFICANCE OF SEQUENTIAL 18F-FDG PET/CT DURING THE TREATMENT OF ANTHRACYCLINE-CONTAINING FRONTLINE CHEMOTHERAPY IN PERIPHERAL T CELL LYMPHOMAS
Authors: Ga-Young Song, Sung-Hoon Jung, Seo-Yeon Ahn, Mihee Kim, Jae-Sook Ahn, Je-Jung Lee, Hyeoung-Joon Kim, Jang Bae Moon, Su Woong Yoo, Seong Young Kwon, Jung-Joon Min, Hee-Seung Bom, Sae-Ryung Kang, Deok Hwan Yang
Journal: HemaSphere (2023)

Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: pite the prognostic significance of 18F-fluorodeoxyglucose (FDG)-positron emission tomography-computed tomography (PET/CT) assessment has important implications on determining the response-adapted therapy in patients with peripheral T-cell lymphomas (PTCLs), an optimal timing of the use and clinical application of PET/CT-based response are still up in the air. Aims: The aim of this study was to explore the prognostic impact of sequential 18F-FDG PET/CT analysis in patients with newly diagnosed PTCLs who treated with frontline anthracycline-based chemotherapy. Methods: One-hundred and forty-three patients with newly diagnosed PTCLs except extranodal NK/T cell lymphoma were included between February 2006 and September 2022. All patients were treated with anthracycline-based chemotherapy. Sequential 18F-FDG PET/CT were obtained at the time of diagnosis, after three cycles of chemotherapy and finally at the end of chemotherapy. Baseline total metabolic tumor volume (TMTV) was computed with the sum of SUV2.5 threshold method, and the interim PET/CT response were assessed using the five-point scale (5-PS) of Deauville criteria. Results: Baseline MTV could be calculated in 126 patients, and median TMTV was 193.9 (range 0.3-3,614.0) cm3. The cut-off value of TMTV was 457.0 cm3 (Sensitivity 45.0%, specificity 74.0%). Patients with high TMTV more than cut-off value had inferior PFS and OS than those with low TMTV (PFS, 9.8 months vs. 26.5 months, HR 1.600, 95% CI 1.010-2.671, p=0.043, Figure 1A; OS, 18.9 months vs. 71.2 months, HR 2.135, 95% CI 1.261-3.615, p=0.004, Figure 1B). Interim 18F-FDG PET/CT assessment was available in all 143 patients. Among 143 patients. When patients were categorized with three subgroups as response with grade 1, grade 2 and 3, and grade 4-5, PFS and OS showed significant difference according to interim visual assessment (PFS, 120.7 months vs. 34.1 months vs. 5.1 months, p<0.001, Figure 1C; OS, not reached vs.61.1 months vs. 12.1 months, p<0.001, Figure 1D). Summary/Conclusion: In conclusion, high baseline TMTV could indicate a poor response to anthracycline-based chemotherapy in PTCLs. Interim PET/CT response based on visual assessment could be a valuable predictive factor of disease progression and survival outcome in the anthracycline-containing treatment of PTCLs. Figure 1. Progression-free survival (A) and overall survival (B) according to the baseline total metabolic tumor volume (TMTV) using a ROC cutoff (457cm3) for TMTV. Progression-free survival (C) and overall survival (D) according to the interim 18F-FDG PET/CT Deauville score.Keywords: Peripheral T-cell lymphoma
PB1738: OBSERVATION OF THERAPEUTIC EFFECT OF BLINATUMOMAB SALVAGE TREATMENT ON B – ALL WITH INVALID OR RECURRENT CART
Authors: Lin Yuehui
Journal: HemaSphere (2023)

Topic: 2. Acute lymphoblastic leukemia - Clinical Background: CART cell therapy is an important means for patients with relapsed and refractory acute B-lymphoblastic leukemia (R/R B-ALL) to obtain remission again, but some patients still have a relapse after CART or CART is ineffective, and the follow-up treatment is very difficult. Aims: To investigate the efficacy of Blinatumomab in the treatment of B ALL which is ineffective or relapsed after CART cell therapy. Methods: Retrospective analyse that from August 2020 to February 2023 ，10 R/R B ALL Who were treated by Blinatumomab after elapse after CART or CART is effective.Among them, 5 were male and 5 were female, with a median age of 45 ys(13-66); PH+ALL 4 cases,PH like ALL 1 case, PH negative ALL 5 cases. All patients were treated with CART cells 1-3 times (including murine CD19-CART, human CD22-CART and human CD19-CART), and the median CART times was 2. Among them, 1 patient relapsed after remission of CART and CART again was ineffective, and 9 patients relapsed after remission of CART; Among them, 3 patients did not undergo allogeneic hematopoietic stem cell transplantation(HSCT), 1 patient underwent secondary HSCT, and all the other patients underwent one HSCT. CD19 was positive confirmed by flow cytometry(FCM) in leukemia cells of all patients. Before Blinatumomab, 5 patients were morphological recurrence, 5 patients were FCM MRD positive. The treatment course of all Blinatumomab is 8-10 days, and the curative effect is evaluated by bone marrow examination after treatment. Results: 10 patients, 1 PH+ALL did not reach CR (10%), 2 PH negative ALL FCM-MRD did not be negative (20%), and 7 patients all reached FCM-MRD negative (70%). Among them, 4 fusion gene（FG） positive patients (3 patients of BCR-ABL1, 1 patient of AML1-ABL1) were all negative in RT PCR. All patients survived safely. Only one patient died of multiple organ failure after Blinatumomab. Summary/Conclusion: R/R B ALL patiants once relapsed again after CART or CART ineffectively with or without HSCT,the treatment is very difficult. Blinatumomab treatment can still make the majority of patients get the chance of remission again. Keywords: BMT, Cancer immunotherapy, Bispecific, Acute lymphoblastic leukemia
P1371: COMPARISON OF DIFFERENT METHODS FOR GENETIC CORRECTION OF GRISCELLI SYNDROME TYPE II-DERIVED STEM CELLS
Authors: Özgür Dogus Erol, Burcu Pervin, Mehmet Emin Şeker, Burcu Özçimen, Şimal Şenocak, Sema Nur Gür, Hasan Basri Kiliç, Merve Gizer, Petek Korkusuz, Nico Peter van Til, Yusuf Çetin Kocaefe, Fatima Aerts Kaya
Journal: HemaSphere (2023)

Topic: 24. Gene therapy, cellular immunotherapy and vaccination - Biology & Translational Research Background: Griscelli Syndrome type 2 (GS-2) is a rare autosomal recessively inherited severe combined immunodeficiency, characterized by partial albinism with or without hemophagocytic lymphohistiocytosis (HLH). It is caused by mutations in the RAB27A gene resulting in mild neutropenia and markedly decreased NK cell and T cell cytotoxicity. Currently the only curative treatment is hematopoietic stem cell (HSC) transplantation. Aims: Here, we aimed to develop gene therapy for correction of stem cells derived from two GS-2 patients with different mutations (exon 3 delAGinsC and exon 7 delCAAGC) in the RAB27A gene, using lentiviral (LV) constructs and CRISPR-Cas9 and assess the potential oncogenic effects of RAB27A overexpression. Methods: GS-2 mesenchymal stem cells (MSCs) were transduced with using a polycistronic LV vector carrying the transcription factors OCT3/4, SOX2, KLF-4 and c-Myc. Induced pluripotent stem cells (iPSCs) were lentivirally transduced with codon optimized RAB27A (RAB27Aco) under the control of three different promoters (PGK, UCOE and SFFV). CRISPR constructs were designed to repair the respective mutations. After correction cells were assessed for RAB27A gene and protein expression. To assess possible development of leukemia, hematopoietic stem cells (HSCs) overexpressing RAB27A were transplanted into Rag2 deficient mice and followed for 6 months. Results: Before correction RAB27A mutations were confirmed in the GS-2 iPSC and MSC cell lines. After correction RAB27A protein expression was detected using FACS and Western blot assays, gene expression was confirmed using qRT-PCR. Correction of the mutation was done using sequencing for the RAB27A gene. As expected, RAB27A expression was highest after transduction with the SFFV promoter, resulting in overexpression of the gene in 50-70% of the cells. Correction using CRISPR-Cas9 was successful in only one of the mutations (delAGinsC). At the interim analysis at three months post transplantation only low levels of RAB27A expression was detected in the peripheral blood of the mice, in the absence of any indications for leukemia. However, more detailed analyses will be performed at sacrifice of the mice at 6 months. Summary/Conclusion: RAB27A gene and protein expression could be detected after LV transduction of GS-2 cells. Both LV gene addition and correction using CRISPR-Cas9 were successful. Interim analysis did not show evidence for leukemia after transplantation of cells overexpressing RAB27A. Keywords: Hematopoietic stem cell, Lentiviral transduction, Stem cell gene therapy, Allogeneic hematopoietic stem cell transplant